In spite of vaccine availability for the past five decades, whooping cough remains a childhood scourge with no available therapy for established disease. Caused by the Bordetella pertussis bacterium, whooping cough is mediated by over twenty virulence factors, none of which provides a clear serological correlate of protection. We hypothesize that appropriately engineered anti-pertussis toxin antibodies will be effective in ameliorating disease. This belief is supported by three lines of evidence: (i) reduced virulence of bacteria lacking pertussis toxin genes; (ii) demonstrated efficacy of the acellular pertussis vaccines (comprised of pertussis toxin and 0-4 additional virulence factors); and (iii) passive immunotherapy studies which have demonstrated protection and even reversal of disease post-infection.
Our specific aims are to: 1. Generate high-affinity humanized, neutralizing anti-pertussis toxin immunoglobulins, 2. Elucidate the structural and functional mechanisms of anti-PT protection, 3. Evaluate pre- and post-exposure protection in mice. This work involves the application of modern protein engineering technologies to an historic disease. The recombinant proteins developed will be superior to previous preparations due to the exclusive inclusion of high-affinity neutralizing antibodies with minimal potential for immunogenicity or viral contamination. We anticipate that the proposed exploratory research will lay the groundwork for phase I clinical trials and that the antibodies created may form the basis of an orphan drug therapeutic. Furthermore, these reagents can be used to probe fundamental questions regarding Bordetella immunity.
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